- Agitation is a subtype of delirium, characterized by an excess of behaviors including aggression, akathisia, disinhibition, and emotional lability.1 Agitation includes a spectrum of behaviors ranging from verbal threats and motor restlessness, to harmful, aggressive, and destructive behaviors. 2
- Aggression, a complex behavior comprised of sensory, emotional, cognitive, and motor elements, can include behaviors that are damaging to individuals or property; attitudes, moods, or gestures that people find threatening or intimidating; or purposeful behavior that is disruptive to social integration.1 Aggression includes verbal aggression, physical aggression toward others, objects, or self. Verbal aggression is most common. 3
- Apathy, generally speaking, is a decrease in or lack of motivation.4 It is also described as a decrease in self-generated, voluntary, and purposeful behaviors.5
- Agitation and aggression can occur within the context of any condition that acutely affects the brain. Such conditions include: traumatic brain injury (TBI), non-traumatic brain injury (including ischemic and thrombotic stroke), anoxia, neuro-degenerative disorders, neoplastic disorders, central nervous system infection, and toxic or metabolic encephalopathy.
- Apathy is seen in multiple psychiatric conditions (including depression and schizophrenia) as well as neurologic disorders (such as Alzheimer’s and other types of dementia), in addition to Parkinson ’s disease, stroke, traumatic brain injury, cerebral infections, and tumors.
- Secondary conditions that commonly occur with TBI and stroke can present as agitation, aggression, or apathy. For example, a severe aphasia often leads to behavioral deficits as the individual is frustrated with the inability to communicate.
Epidemiology including risk factors and primary prevention
- The incidence and prevalence of agitation are dependent on the underlying etiology. Agitation has been estimated to occur in 70% of patients hospitalized with TBI, and approximately one third of patients receiving inpatient rehabilitation for TBI. 6,7 Patients are more likely to have agitation after head injury if they are still in the state of post-traumatic amnesia, if their injury was more severe, if they have a premorbid history of substance abuse,8,9 infection, impaired cognition or lower functional status.9 Agitation has been noted in 20 to 45% of patients with mild cognitive impairment and up to 90% of patients with advanced dementia.10
- Estimates about the epidemiology of aggression also vary with underlying cause. Among patients with severe TBI, the prevalence of aggression has been reported to range from 12-42%,11 but is generally considered to be at least 30%.12 Patients are more likely to have aggression after TBI if they have a pre-injury history of mood disorder, alcohol or substance abuse, frontal lobe lesion, prior episodes of head injuries or history of arrest. 12 Other risk factors for aggression include the presence of delirium, longer period of post-traumatic amnesia, low cognitive status, comorbid medical complications, and impaired language function. Aggression is more common in patients with other neurobehavioral symptoms, such as impulsivity, disinhibition, and sleep issues, then in patients without neurobehavioral symptoms.12 In dementia, the prevalence of aggression has been estimated to range from 20 to 40%. People with dementia who demonstrate aggressive behaviors also tend to have other neuropsychiatric symptoms. Aggression in dementia has also been correlated with disease severity, depression and degree of cognitive impairment. 13,14
- The incidence of apathy varies with the etiology. For example, it occurs in about 36% of post-stroke patients15 and up to 90% in patients who have Alzheimer’s disease.16 In the TBI population, apathy has been present in 20-70% of studied patients, with the average prevalence of 48%.17 In acquired brain injury, there does not seem to be a correlation between apathy and severity of injury or time since injury. 18
- The pathology underlying agitation and aggression is not fully understood and is likely multifactorial. Cerebral structural and chemical abnormalities that have been implicated include: damage to the frontal and temporal lobes, injury to the prefrontal cortex, injury to the thalamus and limbic system, and impaired regulation of serotonin, norepinephrine, and dopamine.8,10,19
- Apathy has been associated with damage to multiple areas of the brain, including the frontal lobe, basal ganglia, and cingulate gyrus. Blockade of dopamine pathways also appear to play a role.20
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- As agitation, aggression, and apathy are often sequela of various diseases and injuries, improvement can be seen with recovery of the underlying etiology. However, ongoing and potentially worsening agitation, aggression, and apathy may be seen in progressive diseases.
- Agitation following TBI tends to resolve when the delirium resolves. In progressive neurodegenerative disorders, including dementia, agitation may be an ongoing problem.
- Aggression following TBI can either resolve when the agitation resolves or remain an ongoing problem. In progressive neurodegenerative disorders, including dementia, aggression may be an ongoing problem.
- Apathy may improve if the underlying condition resolves or is adequately treated.
Specific secondary or associated conditions and complications
Agitation and aggression can have dramatically deleterious sequelae for patients with TBI and other acquired brain injuries. Agitation and aggression have been associated with interruptions and disruptions of care. These behavioral changes have also been correlated with increased lengths of stay in both hospital and acute rehabilitation settings. These patients pose a special challenge for traditional brain injury rehabilitation units, which are generally unlocked and also care for other vulnerable patients. Aggression, then, can be a barrier to admission to acute rehabilitation and to success in acute rehabilitation programs.11 The overall cost of care can be increased. There is also a high potential for injury to the patient or others. The burden on caregivers can be more intense when a patient is agitated or aggressive. Agitation and aggression can also lead to significant social issues, including alienation from family and loss of employment. Further, there can be difficult legal issues, which can be exaggerated if the patient engages in criminal activity.1,8,19,21
Essentials of Assessment
For patients with agitation and aggression, a detailed history should include the history of the inciting injury or disease, social history (including education, employment), medical history (including neurological, psychiatric and endocrine systems), sleep history, nutritional status, and pain assessment. History of substance abuse, including drugs, tobacco, and alcohol use, are important as withdrawal, craving, and other sequela of use could contribute to the patient’s agitation and aggression. In addition to the patient’s reports of agitation and aggression, it is also helpful to get input from other observers, such as caregivers.
Efforts should be made to communicate directly with the patient to elicit history. This is important to not only better understand their history, but may also reduce patient’s frustrations that they are not being included in their care. Techniques such as the utilization of yes/no questions may be indicated in the setting of aphasia or other communication barriers.
For patients with apathy, the history should include past medical history (including history of psychiatric illness), personality changes, and progression of disease. To rule out a potentially treatable cause of apathy, screening for depression should be done early.
For agitation and aggression, the physical exam should include vital signs (may be abnormal in cases of infection or medical instability), neurological examination (could provide focal findings or clues to the underlying pathology), cardiovascular and pulmonary evaluations (acute medical issues), and musculoskeletal examination (potential sources of discomfort or pain). Assessment for aphasia, hallucinations, memory deficits, and other issues may yield clues about agitation and aggression.
Patients with agitation and aggression require careful functional assessments. Agitation and aggression are associated with abnormalities in executive function, impulse regulation, and impaired ability to perform basic self-care tasks. Further, the behaviors associated with agitation and aggression can interfere with caregiving activities in patients who would benefit from assistance. The negative effect on ability to function can be profound.3,11 Ranchos Los Amigos scale may be helpful in categorizing TBI patient’s recovery progression and for communicating their status with other team members.
For apathy, the patient’s affect as well as what they do from a functional standpoint should be assessed. It is important to differentiate whether patients are not doing activities of daily living (ADLs)/self-care because they are not motivated, or not being able to remember to do those tasks due to cognitive impairment or lack of insight.
For agitation and aggression, the basic laboratory work-up would start with chemistry and complete blood count to evaluate for common metabolic or hematologic abnormalities. Other tests may be required to evaluate for specific metabolic problems and infectious issues. Cerebrospinal fluid analysis may be warranted, particularly if the underlying cause of the agitation or aggression is thought to be infectious, inflammatory, or related to a paraneoplastic syndrome.
For patients with agitation and aggression, brain imaging such as CT or MRI would be needed to ascertain an underlying etiology if it were not already known. If the agitation or aggression is possibly due to pain, x-rays can evaluate for previously undiagnosed fractures or heterotopic ossification.
Supplemental assessment tools
- Agitation: For patients with TBI, the Agitated Behavior Scale can help clinicians quantify the agitated behaviors at a certain point in time and over a period of time. 22 For patients with dementia, the Pittsburgh Agitation Scale or Behavioral Pathology in Alzheimer’ s disease Rating Scale may be helpful.23
- Aggression: Commonly used tools include the Neurobehavioral Functioning Inventory, Neuropsychiatric Inventory, Neurobehavioral Rating Scale, and the Overt Aggression Scale-Modified for Neurorehabilitation. 3
- Apathy: There are multiple available assessment tools, including the Apathy Evaluation Scale, the Apathy Scale, and the Apathy Inventory. Furthermore, the Neuropsychiatric Inventory and the Unified Parkinson’s Disease Rating Scale both assess apathy as part of their overall measure.5,16
- Frontal seizures can be mistaken as behavioral issues. In some cases, an electroencephalogram (EEG) may, therefore, be indicated.
Agitation and aggression can be impacted both positively and negatively by environmental issues. These include the amount of stimulation, light and noise levels, space and privacy issues, and interactions with staff members, other patients, and family/friends.21,24 Environmental interventions can be helpful in management
Rehabilitation Management and Treatments
At different disease stages
- For agitation and aggression, interventions should first include modifying the environment (reduction of stimuli including televisions and phones, visitors, other patients, and medical equipment), normalizing the sleep-wake cycles, optimizing nutrition, and avoiding physical restraints.24 If further intervention is needed, beta-blockers and antiepileptics with mood regulatory effects (such as carbamazepine or valproate) may be considered. Neuroleptics, antidepressants, benzodiazepines, and buspirone are considered second-line treatments. 25 However, in acute brain-injured patients, it is recommended that benzodiazepines and typical antipsychotics be avoided if possible, as they may inhibit cognitive recovery.26,27,28. For chronic TBI patients with aggression not accompanied by anger, amantadine may provide some benefit.29,30 Other medications that can be trialed for chronic aggression in the brain injury population include beta blockers and methylphenidate. 29 Cognitive behavioral therapy has demonstrated benefits for aggression. Interventions, including group and individual therapies focused on anger education and self-monitoring, likely help by optimizing self-awareness and also by helping patients track, check, and reduce their aggressive comments and other behaviors.11
- For apathy, there are no FDA-approved medication treatments. Some small studies and case reports have demonstrated possible beneficial effects of certain medications. These include anti-cholinesterase inhibitors such as rivastigmine, donepezil, and galantamine and psychostimulants such as methylphenidate, modafinil and armodafinil. Antidepressants, especially more activating ones, are also used in this population.5
Coordination of care
The interdisciplinary treatment team includes the physician, nurse, occupational therapist, physical therapist, recreation therapist, speech and language pathologist, neuropsychologist and others. Care can be provided in a variety of settings, including inpatient rehabilitation units, outpatient therapies, structured day programs, residential treatment, inpatient psychiatric treatment, and in-home cognitive services.28
Cognitive rehabilitation can be a particularly important part of functional recovery when agitation, aggression, or apathy occur. An international panel of experts in cognitive rehabilitation after TBI (INCOG) has developed guidelines for patients with moderate to severe TBI who have cleared post-traumatic amnesia but have ongoing cognitive sequelae. These guidelines can provide a framework for clinicians who are planning, providing, and evaluating therapies to affected individuals.31
Patient & family education
In cases of acute brain injury, where the agitation or aggression may be transient and is consistent with stages of recovery, family members need education about the situation. Visitors are also part of the therapeutic environment, so their visits may need to be shortened or scheduled around rest periods for the patient. Families should have knowledge of potential situations that trigger agitated or aggressive behaviors so these can be avoided.32 In cases of neurodegenerative injury, including dementia, families need education about the expected prognosis and time course. They may need assistance setting up ongoing care for the patient.10
Cutting Edge/ Emerging and Unique Concepts and Practice
For agitation and aggression, there have been reports of the successful use of electroconvulsive therapy. Complementary and alternative therapy modalities, including massage therapy and essential oils, have also been implemented.24 However, these trials have not been large or generalizable enough to be widely applied. Additional research is needed.
In a small study, neuromodulation with repetitive transcranial magnetic stimulation has shown benefit as a treatment modality for apathy in patients with Alzheimer’s disease.33 More research is needed though to determine if neuromodulation is beneficial in other disease processes that result in apathy.
Providing care via telehealth or other virtual means can be helpful for people with brain injuries and their families. As technology becomes available, patients and clinicians become more comfortable using it, and other logistics and barriers (such insurance, licensure) are addressed, this new way of delivering care may become even more common. Neuropsychiatric sequelae, including aggression, can be assessed. Cognitive behavior therapy and related interventions, along with family education, can be provided. This may help people with chronic effects of brain injury, who may have difficulty coming in to the clinic regularly, access essential and beneficial care. 34
Gaps in the Evidence- Based Knowledge
For aggression and agitation following traumatic and acquired brain injury, there are many unsettled questions for rehabilitation clinicians and investigators to consider. It is possible that future therapies could shorten the length of the agitated and aggressive period of recovery, thereby lessening the burden of these conditions. This clinical area would benefit from studies utilizing consistent nosology and methodology to facilitate generalizability.28,32
- Sandel E, Mysiw WJ. The agitated brain injured patient. Part 1: Definitions, differential diagnosis, and assessment. Arch Phys Med Rehabil. 1996;77:617-623.
- Beasley L, Beasley PJ. Agitation. In: Zaoutis LB, Chiang VW, eds. Comprehensive Pediatric Hospital Medicine. 2007. Mosby.
- Whitwam S, Jones KA. Assessing aggression following acquired brain injury: A systematic review of assessment measures. 2019; 33: 1491-1502.
- Marin RS, Wilkosz PA. Disorders of diminished motivation. In: Silver JM, McAllister TW, Yudofsky SC, eds. Textbook of Traumatic Brain Injury, 2nd Ed. 2011. Washington, DC: American Psychiatric Publishing Inc.
- Levy R & Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cerebral Cortex. 2006; 16(7): 916-928
- McNett M, Sarver W, Wilczewski P. The prevalence, treatment and outcomes of agitation among patients with brain injury admitted to acute care units. Brain Injury 2012; 26(9), 1155-1162.
- Singh R, Venjateshwara G, Nair KPS, Khan M, Saad R. Agitation after traumatic brain injury and predictors of outcome. Brain Inj 2014; 28:336-340.
- Lombard LA, Zafonte RD. Agitation after traumatic brain injury. Am J Phys Med Rehabil. 2005;84:797-812.
- Bogner J, Barrett RS, Hammond FM et al. Predictors of agitated behavior during inpatient rehabilitation for traumatic brain injury. Arch Phys Med Rehabil 2015; 96 (8 Suppl 3): S274-281.
- Desai AK, Schwartz L, Grossberg GT. Behavioral disturbance in dementia. Curr Psychiatry Rep. 2012;14:298-309.
- Iruthayarajah J, Alibrahim F, Mehta S, et al. Cognitive behavioral therapy for aggression among individuals with moderate to severe acquired brain injury: A systematic review and meta-analysis. Brain Inj 2018; 32(12), 1443-1449.
- Roy D, Vaishnavi S, Han D, Rao V. Correlates and prevalence of aggression at six months and one year after first-time traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2017; 29: 334-342.
- Choi SSW, Budhathoki C, Gitlin LN. Co-occurrence and predictors of three commonly occurring behavioral symptoms in dementia: Agitation, aggression, and rejection of care. Am J Geriatr Psychiatry. 2017; 25: 459-468.
- Wolf MU, Goldberg Y, Freedman M. Aggression and agitation in dementia. Am Acad Neurol Continuum Journal. 2018; 783-803.
- Caeiro L, Ferro JM, Costa J. Apathy secondary to stroke: a systemic review and meta-analysis. Cerebrovasc Dis. 2013;35:23-39.
- Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry. 2012;20:104-122.
- Arnould A, Rochat L, Azouvi P, & Van der Linden M. A multidimensional approach to apathy after traumatic brain injury. Neuropsychol Rev. 2013; 23:210-233.
- Worthington A, Wood RLL. Apathy following traumatic brain injury: a review. Neuropsychologia. (2018) 118:40–7.
- Ciurli P, Formisano R, Bivona U, Cantagallo A, Angelelli P. Neuropsychiatric disorders in persons with severe traumatic brain injury: Prevalence, phenomenology, and relationship with demographic, clinical, and functional features. J Head Trauma Rehabil. 2011;26:116-126.
- Chase T. Apathy in neuropsychiatric disease: Diagnosis, pathophysiology and treatment. Neurotox Res 2011; 19: 266-278.
- Mysiw WJ, Sandel E. The agitated brain injured patient. Part 2: Pathophysiology and management. Arch Phys Med Rehabil. 1997;78 :213-220.
- Corrigan JD. Development of a scale for assessment of agitation following traumatic brain injury. J Clin Exp Neuropsychol. 1989;11:261-267.
- Rosen J, Burgio L, Kollar M, Cain M, Allison M, Fogleman M, Michael M, Zubenko GS. The Pittsburgh Agitation Scale: A User-Friendly Instrument for Rating Agitation in Dementia Patients. Am J Geriatr Psychiatry. 1994 Winter;2(1):52-59.
- Duraski SA. Nonpharmacologica management of agitated behaviors after traumatic brain injury. Rehabil Nurs 2011; 36: 135-145.
- Luauté J, Plantier D, Wiart L, Tell L; SOFMER group. Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med. 2016 Feb;59(1):58-67.
- Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury: A state of the art review. J Rehabil Res Dev. 2009;46:851-879.
- Fleminger S, Greenwood RRJ, Oliver DL. Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane review 2008. Wiley.
- Levy M, Berson A, Cook T, et al. Treatment of agitation following traumatic brain injury: A review of the literature. NeuroRehabilitation. 2005;20:279-306.
- Hammond FM, Bickett AJ, Norton JH, Pershad R. Effectiveness of amantadine hydrochloride in the reduction of chronic traumatic brain injury irritability and aggression. J Head Trauma Rehabil. 2014; 29: 391-399.
- Hammond FM, Malec JM, Zafonte RD, et al. Potential impact of amantadine on aggression in chronic traumatic brain injury. J Head Trauma Rehabil. 2017; 32: 302-318.
- Bayley MT, Tate R, Douglas JM, et al. INCOG guidelines for cognitive rehabilitation following traumatic brain injury: Methods and overview. J Head Trauma Rehabil. 2014; 29: 290-306.
- Kim E, Lauterback EC, Reeve A, et al. Neuropsychiatric complications of traumatic brain injury: A critical review of the literature (Report by the ANPA Committee on Research). J Neuropsychiatry Clin Neurosci. 2007;19:106-127.
- Padala PR, Boozer EM, Lensing SY, et al. Neuromodulation for apathy in Alzheimer’s Disease: A double-blind, randomized, sham-controlled pilot study. J. Alzheimer’s Disease. 2020; 77:1483-1493
- McDonald S, Trimmer E, Newby J, Grant S, Gertler P, Simpson-Grahame K. Providing on-line support to families of people with brain injury and challenging behavior: A feasibility study. Neuropsychol Rehabil. 2021; 31: 392-413.
Original Version of the Topic
Joseph A. Rosenthal, MD. Agitation/aggression/apathy after brain injury and other CNS disorders. Publication Date: 9/20/2013.
Previous Revision(s) of the Topic
Joseph A. Rosenthal, MD, Diane Mortimer, MD. Agitation/aggression/apathy after brain injury and other CNS disorders. Publication Date: 8/19/2016.
Joseph A. Rosenthal, MD
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Diane Mortimer, MD
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Karen Woods, MD
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